Metals in Host–Microbe Interaction: The Host Perspective

This overview covers the role of the metal ions in infectious diseases, focusing on iron (Fe), copper (Cu), zinc (Zn), and, to a lesser extent, manganese (Mn) and the metalloid selenium (Se). In addition, recommended dietary allowances are addressed, as are metal-based drugs for the treatment of tropical diseases. The human organism binds essential metals such as iron, manganese, copper, and zinc to specific compounds (including proteins) in order to withhold these metals from invading pathogens (“nutritional immunity”); in this way, metal binding provides resistance to infection. Selenium status can also affect the host–pathogen interaction, but pathogens have mechanisms to counteract this protective potency. As alternative to a withdrawal of metals, microbes can be exposed to particularly high—and thus toxic—levels of metal ions. A secondary protective mechanism stems from the production (by host innate immune cells) of reactive oxygen and nitrogen species; this can also result in host tissue damage. In addition, the gasotransmitters nitric oxide (an oxidant) and carbon monoxide are indirectly involved in side effects (deprotection and protection, respectively, of bound heme) that result from the immune response. Host-mediated alteration of Fe homeostasis directly impacts on the proliferation of microbes. Depending on the type of pathogen, different regulatory mechanisms can be initiated. Limiting the availability of iron can be an efficient strategy to restrict extracellular bacteria, although such a strategy is detrimental for intracellular pathogens. Iron homeostasis is partly linked to Cu homeostasis. Copper deficiency predisposes mammals to infectious diseases, to some extent as a consequence of a lack of neutrophils induced by inadequate Cu availability or supply. Finally, there is a clear-cut correlation between bacterial infections and Zn removal from serum. More generally, Zn deficiency reduces immune defense against infections, chronic inflammatory disease, and reduced cellular activation, whereas high levels of zinc can hamper effective signal transduction. Due to the epidemic proportions of tropical diseases (e.g., leishmaniasis, Chagas disease, and malaria) and lack of effective treatment, drugs are being developed that are based on coordination compounds of metals, including copper, iron, ruthenium, and gold. These metals are coordinated to aromatic ligand systems that allow for a stabilization of the drug, during the drug’s transport to its target, and eventually intercalation into DNA. For malaria, the increasing resistance of the malaria parasite against the classical drug chloroquine may be overcome by employing ferrocenyl derivatives of chloroquine.